CN101817787B - Androgen receptor antagonist for resisting prostate cancer - Google Patents
Androgen receptor antagonist for resisting prostate cancer Download PDFInfo
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- CN101817787B CN101817787B CN 201010120494 CN201010120494A CN101817787B CN 101817787 B CN101817787 B CN 101817787B CN 201010120494 CN201010120494 CN 201010120494 CN 201010120494 A CN201010120494 A CN 201010120494A CN 101817787 B CN101817787 B CN 101817787B
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- prostate cancer
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Abstract
The invention provides an androgen receptor antagonist for resisting the prostate cancer, relates to a sulfoimidazoledione with substituted groups on two nitrogen atoms, and relates to a use of such the compounds as a medicament for treating the diseases or disorders related to the androgen receptor, such as prostate cancer, alopecia or whelk.
Description
Technical field
The present invention relates to a class thiocarbamoyl imidazole diketone, two nitrogen-atoms all has substituted radical; And relate to the such compound of use as pharmacological agent androgen receptor (Androgen Receptor, ' AR ') relevant disease or imbalance, for example prostate cancer, alopecia or comedo.
Background technology
(androgen receptor is a trans transcription regulatory protein that the ligand dependent of 110,000 Dalton molecular weights is arranged AR) to androgen receptor, belongs to steroid hormone nuclear receptor superfamily member, mainly is present in the nuclear of target cell.Androgen receptor is all to play the part of important effect in the pathogeny of prostate cancer or its deterioration process.It and special steroid hormone aglucon such as testis cave or more effective pair of hydrogen testis cave (DTH) are in the combination of ligand binding domain, cause conformational change, thereby (hsp) dissociates with heat shock protein(HSP), cause that the androgen receptor activation makes it to increase with DNA avidity, the activatory androgen receptor combines with specific dna sequence dna-androgen response element (ARE) in dimeric forms and the target cell nuclear, and in nucleus, move and other transcription factor interaction, thereby the adjusting target gene expression, the propagation of pair cell, existence and differentiation produce corresponding biological effect.Androgen receptor is played an important role in the relevant disease of many male hormones, for example prostate cancer, benign prostate enlargement, comedo and male pattern baldness etc.
Having the optionally main effect of androgen receptor antagonist (AR antagonist) is directly to stop testis cave or Standone (DHT) to combine with androgen receptor, the effect of blocking-up male sex hormone pair cell, make cell produce " hunger " phenomenon, thereby make apoptosis.It can be used for: a) male contraception; B) for example sexual desire is crossed strong and the sexual desire imbalance in the imbalance that a series of male hormones of treatment are relevant; C) treatment comprises illnesss such as benign prostate enlargement, comedo, bald and hair hyperplasia; D) prevent to reduce for example heating after the castration of relevant symptom with male hormone; E) be specifically designed to and prevent from or suppress the muscle of sex change women in commentaries on classics property therapeutic process to increase; F) anticancer change growth medicine and cooperation hormonotherapy treatment prostate cancer; G) prevention, prevention or elimination prostate cancer.
Prostate cancer is in sickness rate first mortality ratio the second in male sex's malignant tumour, only just there are 186320 new patients with prostate cancer in the U.S. in 2008 by diagnosis and therefore 26660 patients die.Though the sickness rate of China is far below the west, along with improving constantly of standard of living and diagnostic techniques, the sickness rate of prostate cancer is continuous ascendant trend.Prostate cancer is a kind of progress malignant tumour more rapidly, if can not get early stage diagnosis and treatment, from finding symptom, average survival time has only 3～5 years.On the concrete grammar of prostate cancer therapy, operation castration { radical prostatectomy (TLRRP), transurethral prostatectomy (TURP) and bilateral orchidectomy } and medicine castration { r-hLH (LHRH) antagonist and gonadotropin releasing hormone (GnRH) antagonist } be the first-selected means for the treatment of at the initial stage, simultaneously in conjunction with methods of treatment such as internal secretion, immunity, differentiation, gene and radiation.The male sex hormone major part is from testis, and small part is from suprarenal gland; The surgery castration can only be removed the male sex hormone from testis, and suprarenal gland still can be secreted a large amount of steroidals and produce some male sex hormones and enter prostata tissue and be released in the blood.Prostate cancer has higher susceptibility to male sex hormone.In order to reach the purpose for the treatment of prostate cancer, must suppress androgenic synthetic, the interaction of prevention and endonuclear androgen receptor (AR), thus block androgenic physiological action.Common male sex hormone blocking treatment (ADT) mainly carries out round this gonad axis of hypothalamus-hypophysis-testis that male sex hormone produces, and pharmacological agent is divided into: 1) endocrine axis blocking treatment; 2) directly suppressing male sex hormone synthesizes and 3) androgen receptor antagonists.Androgen receptor antagonists (AR Antagonist) and antiandrogen drug combination, be prostate cancer (the Castration Resistant Prostate Cancer that present stage control castration lost efficacy, be called for short CRPC) the most effective drug treatment, it begins all very effective to most advanced prostate cancer, but prostate cancer cell finally can adapt to the environment of lower concentration male hormone and treatment is produced resistance, and result's prostate cancer in three to five years almost all can recur and cause death in these all patients.
Androgen receptor antagonist (AR antagonist) the medicine for example initial design of Ni Lumi amine (Niluamide), flutamide (Flutamide) and bicalutamide (Bicalutamide, trade name Casodex) is to be used for avoiding the side effect of hormonotherapy and the resistance of eliminating the prostate cancer patient.Although these androgen receptor antagonists are respond well to the advanced prostate cancer patient who receives treatment first when being used with hormonotherapy, still be that the prostate cancer curative effect of their antagonism property of medicine of combination therapy is very limited no matter as using separately.Recent study shows, bicalutamide as the specificity of androgen receptor (AR) antagonist a little less than, and certain activated receptor effect (agonism) (flutamide also has been found similar problem) is arranged.Current research shows that reactivating of androgen receptor signalling channel may be the basic reason that hormonotherapy is developed immunity to drugs, it has limited for example curative effect of bicalutamide treatment prostate cancer of androgen receptor antagonist medicine that existing market generally uses, particularly for resistivity prostate cancer in late period.In addition, the curative effect of these androgen receptor antagonist medicines also generally is subject to their pronounced side effects, and is for example toxic to liver or central nervous system.So the prostate cancer clinical treatment presses for the high reactivity hypotoxicity and does not have the androgen receptor antagonist of new generation of remaining activating property (agonism).Among the present invention, on chemical structure, replace classical androgen receptor as 4-trifluoromethylbenzonitrile and trifluoromethyl nitrobenzene in conjunction with element, might improve specificity and reduce or eliminate the androgen receptor antagonist Side effects of pharmaceutical drugs used the clinically now toxicity of liver or central nervous system (for example to), these compounds can combine with androgen receptor, the inhibition acceptor moves in nucleus and reduces its transcriptional activity, is expected to become the androgen receptor antagonism drug candidate of treatment advanced prostate cancer.
Summary of the invention
The present invention includes compound, use this compounds (salt that comprises them) and pharmaceutical composition thereof method as androgen receptor antagonist (AR antagonist) with following chemical structure of general formula (I).
Compound with chemical structure of general formula (I):
R wherein
1Be selected from
Wherein R ' is methyl, ethyl or CF
3Y is methyl, CF
3, cyano group or halogen;
Wherein W is Sauerstoffatom, sulphur atom or two hydrogen atoms;
R wherein
3And R
4Be that independently methyl or they form a C together separately
3-5Cycloalkyl;
R wherein
2Be selected from such as the aromatic base of phenyl and substituent thereof, such as the assorted aromatic base of pyridine and substituent, alkyl and substituent thereof, such as the saturated heterocyclic and the substituent thereof of 3-or 4-pyridine or tetrahydropyrans or 3-tetramethyleneimine or tetrahydrofuran (THF).
Compound with chemical structure of general formula (I), R
1Be selected from
Wherein R ' is methyl, ethyl or CF
3Y ' is methyl, CF
3
R wherein
3And R
4Form C together
3-5Cycloalkyl.
Compound with chemical structure of general formula (I), R
1Be selected from
Y " be cyano group or halogen.
Compound with chemical structure of general formula (I), wherein R
2Be aromatic base and have following substituted radical :-C (O) NHR " ,-C (O) OR " ,-SO
2Me ,-SO
2NHR ", cyano group, hydroxyl, alkoxyl group ,-C (S) NHR " ,-C (O) OR ", halogen or 5 to 6 yuan of assorted aromatic bases; R wherein " be selected from hydrogen atom, C
1-6Alkyl, C
1-6Cycloalkyl or C
1-6Thiazolinyl.
Compound with chemical structure of general formula (I), wherein R
2Be assorted aromatic base and have following substituted radical :-C (O) NHR " ,-C (O) OR " ,-SO
2Me ,-SO
2NHR ", cyano group, hydroxyl, alkoxyl group ,-C (S) NHR " ,-C (O) OR ", halogen or 5 to 6 yuan of assorted aromatic bases; R wherein " be selected from hydrogen atom, C
1-6Alkyl, C
1-6Cycloalkyl or C
1-6Thiazolinyl.
Above compound has following chemical structure of general formula (II)
R wherein
1' be selected from
Wherein R ' is methyl, ethyl or CF
3Y ' is methyl, CF
3
R wherein
3' and R
4' form C together
3-5Cycloalkyl;
Wherein B is selected from cyano group, methyl, CF
3Or halogen;
Wherein A is selected from-C (O) NHCH
3,-C (O) NH
2,-C (O) OCH
3,-C (O)) CH
2CH
3, cyano group, hydroxyl, alkoxyl group ,-SO
2Me, methyl ,-SO
2NHMe or-SO
2NH
2
Wherein W is a Sauerstoffatom.
Compound also can have following chemical structure of general formula (III)
R wherein
1" be selected from
Y " be cyano group or halogen;
Wherein B is selected from cyano group, methyl, CF
3Or halogen;
Wherein A is selected from-C (O) NHCH
3,-C (O) NH
2,-C (O) OCH
3,-C (O)) CH
2CH
3, cyano group, hydroxyl, alkoxyl group ,-SO
2Me, methyl ,-SO
2NHMe or-SO
2NH
2
Wherein W is a Sauerstoffatom.
Compound also can have following chemical structural formula
The present invention includes the synthetic top method of describing compound.
Use with the compound or pharmaceutically acceptable salt thereof among the present invention or prodrug pharmaceutical composition as activeconstituents, the method of the active associated conditions of treatment and androgen receptor comprises treatment prostate cancer (comprising responsive and insensitive patient to hormonotherapy), alopecia, dark sore and comedo etc.
Description of drawings
Accompanying drawing 1 is the medicine kinetics behind oral example 6 compounds of mouse, has shown blood substance concentration over time.
Embodiment
Synthesizing of compound
The compound that the present invention has chemical structure of general formula (I) can prepare with synthetic route that describes below and condition.
General synthetic route 1
Shown in the as above general synthetic route 1, isothiocyanic acid acyl ester 3 (isothiocyanate) can obtain by aniline 1 and thiophosgene (thiophosgene) reaction.The preparation of intermediate 6 is by under the situation that has TMSCN or sodium cyanide to exist aniline 4 (or alkyl ammonia) and ketone 5 being dewatered.This step condensation reaction also can be by reacting with aniline 4 (or alkyl ammonia) and corresponding ketone cyanalcohol (ketonecyanohydrin) under the situation that has sal epsom to exist.Final product thio-hydantoin (chemical structure of general formula I) can obtain from the reaction of intermediate 3 and intermediate 6.Aniline or alkyl ammonia 1 can be bought and obtain or with known references method preparation (for example reduce oil of mirbane).
Synthesizing of example 1
Synthesizing of 4-isothiocyanic acid-3-trifluoromethoxy-benzonitrile (intermediate 3a)
Thiophosgene (4.21g, slowly add in aqeous suspension 36.6mmol) (30mL) 4-amino-2-methyl-benzonitrile 1a (5g, 34.9mmol).The mixture that obtains after stirring one hour, room temperature (25oC) is used ethyl acetate extraction three times (3 * 25mL).Merge organic layer, and washing (1 * 50mL), dry (MgSO4), vacuum is drained and is obtained light brown solid 3a (intermediate 7,6.5g, 100% yield), is directly used in next step reaction.
Synthesizing of 2-fluoro-N-methyl-4-nitro-benzamide (intermediate 8)
(15g, (20g, (DMF, 20mL) solution is at-5 ℃ for dimethyl formamide 110mmol) 130mmol) to splash into 2-fluoro-4-nitro-phenylformic acid 7 slowly with sulfur oxychloride.Stir dropwise add after 1 hour methylamine (400mL, 800mmol).Slowly be warmed up to room temperature.To going into the 125ml frozen water, ethyl acetate extraction, the salt water washing, dried over mgso concentrates, and crystallization obtains yellow solid compound 8 (20g, 90%).
1H NMR(acetone-d
6，500MHz)δ(ppm)7.66(1H，dd，J＝8.5，8.5Hz)，6.41(1H，dd，J＝8.6，2.1Hz)，6.32(1H，dd，J＝13.6，2.0Hz)，3.05(3H，d，J＝4.4Hz)。Mass spectrum: 163 (M+H
+).
Synthesizing of 4-amino-2-fluoro-N-methyl-benzamide (intermediate 9)
(3g 15.1mmol) is dissolved in the solution of ethyl acetate and acetate (12mL+12mL) with compound 8.Add the 8g iron powder and reflux, LCMS detects, and finishes cool to room temperature until reaction.Cross filter solid, the ethyl acetate washing solid with 50mL merges organic phase, the salt water washing, and dried over mgso concentrates, and obtains yellow solid compound 9 (2.5g, 97%).
1H NMR(acetone-d
6，500MHz)：δ(ppm)7.69(1H，dd，J＝8.7，8.8Hz)，7.15(1H，s)，6.51(1H，dd，J＝8.6，2.1Hz)，6.38(1H，dd，J＝14.7，2.1Hz)，5.70(1H，br s)，2.88(3H，d，J＝4.3Hz)。Mass spectrum: 169 (M+H
+).
Synthesizing of 4-(1-cyano group-ring fourth amino)-2-fluoro-N-methyl-benzamide (intermediate 10)
With TMS-CN (29.7g, 300mmol), cyclobutanone (14g, 200mmol), compound 9 (16.8g 100mmol) is dissolved in the 200mL acetate, heat 80 ℃ 24 hours.Reaction finishes the back and adds 200mL water, uses ethyl acetate extraction, the salt water washing, and dried over mgso concentrates, and with normal hexane and ether (20mL-20mL) washing, filters and obtains product 10 (20g, 84%).
1H NMR(CDCl
3，300MHz)：δ(ppm)7.92(1H，dd，J＝8.4，8.4Hz)，6.76(1H，q，J＝4.3Hz)，6.48(1H，dd，J＝8.3，1.9Hz)，6.29(1H，dd，J＝14.3，1.9Hz)，4.72(1H，br s)，2.97(3H，d，J＝4.4Hz)，2.85-2.75(2H，m)，2.4-2.35(2H，m)，2.3-2.15(1H，m)，1.95-1.85(1H，m)。Mass spectrum: 246 (M-H).
4-[7-(4-cyano group-2-trifluoromethoxy-phenyl)-8-oxo-6-sulfo--5,7-diaza spiro [3,4] octane-5-
Base]-2-fluoro-N-methyl-benzamide (example 1) synthetic
Example 1
With compound 10 (392mg, 1.58mmol) and 3a (494mg 2.02mmol) is dissolved in DMF (5mL), 110 ℃ of microwave heatings, 12h.Add methyl alcohol (10mL) and HCl (2N, 5mL) reflux 1h.Ethyl acetate extraction, the salt water washing, dried over mgso concentrates.PE: EA/1: 1 crosses post obtains examples of compounds 1 (250mg, 25%).
1H NMR(CDCl
3，500MHz)：δ(ppm)8.30(1H，dd，J＝8.6，3.5Hz)，7.70(2H，dd，J＝8.0，1.5Hz)，7.63(1H，d，J＝8.5Hz)，7.26(1H，m)，7.15(1H，dd，J＝11.5，1.5Hz)，6.60(1H，br s)，3.00(3H，d，J＝5Hz)，2.65(2H，m)，2.52(2H，m)，2.27(1H，m)，1.70(1H，m)。Mass spectrum: 493 (M+H).
4-[7-(4-cyano group-2-fluoro-phenyl)-8-oxo-6-sulfo--5,7-diaza spiro [3,4] octane-5-yl]-2-
Synthesizing of fluoro-N-methyl-benzamide (example 2)
Example 2
Example 2 is to obtain with the reaction by intermediate 10 and 7b of the method for similar synthetic example 1 that (yield: 23%), 7b is that the method with similar synthetic 7a obtains from corresponding aniline reaction.
1H NMR (CDCl
3, 500MHz): δ (ppm) 8.30 (1H, dd, J=8.6,3.5Hz), 7.57 (3H, m), 7.26 (1H, m), 7.15 (1H, dd, J=12.0,2.0Hz), 6.71 (1H, br s), 3.00 (3H, d, J=5Hz), 2.65 (2H, m), 2.52 (2H, m), 2.27 (1H, m), 1.70 (1H, br m). mass spectrum: 427 (M+H
+).
4-[7-(4-cyano group-2-methyl-phenyl)-8-oxo-6-sulfo--5,7-diaza spiro [3,4] octane-5-yl]-
Synthesizing of 2-fluoro-N-methyl-benzamide (example 3)
Example 3
Example 3 is to obtain with the reaction by intermediate 10 and 7c of the method for similar synthetic example 1 that (yield: 21%), 7c is that the method with similar synthetic 7a obtains from corresponding aniline reaction.
1H NMR (CDCl
3, 500MHz): δ (ppm) 8.30 (1H, dd, J=8.6,3.5Hz), 7.67 (2H, m), 7.38 (1H, d, J=8.0Hz), 7.26 (1H, m), 7.20 (1H, dd, J=11.5,2.0Hz), 6.71 (1H, br s), 3.00 (3H, d, J=5Hz), 2.65 (2H, m), 2.52 (2H, m),, 2.15 (3H, s), 2.15 (1H, m), 1.68 (1H, br m). mass spectrum: 423 (M+H
+).
4-[7-(4-cyano group-2-trifluoromethyl-phenyl)-8-oxo-6-sulfo--5,7-diaza spiro [3,4] octane-5-
Base]-2-fluoro-N-methyl-benzamide (example 4) synthetic
Example 4
Example 4 is to obtain with the reaction by intermediate 10 and 7d of the method for similar synthetic example 1 that (yield: 22%), 7d is that the method with similar synthetic 7a obtains from corresponding aniline reaction.
1H NMR(CDCl
3，500MHz)：δ(ppm)8.30(1H，dd，J＝8.6，3.5Hz)，8.12(1H，d，J＝1.5Hz)，8.01(1H，dd，J＝8.5，2.0Hz)，7.58(1H，d，J＝8.0Hz)，7.26(1H，m.br)，7.15(1H，dd，J＝11.5，2.0Hz)，6.71(1H，br s)，3.00(3H，d，J＝5Hz)，2.70(2H，m)，2.52(2H，m)，2.15(1H，m)，1.68(1H，br m)。Mass spectrum: 477 (M+H
+).
4-[7-(4-cyano group-2-chloro-phenyl)-8-oxo-6-sulfo--5,7-diaza spiro [3,4] octane-5-yl]-2-
Synthesizing of fluoro-N-methyl-benzamide (example 5)
Example 5
Example 5 is to obtain with the reaction by intermediate 10 and 7e of the method for similar synthetic example 1 that (yield: 23%), 7e is that the method with similar synthetic 7a obtains from corresponding aniline reaction.
1H NMR(CDCl
3，500MHz)：δ(ppm)8.39(1H，t，J＝9.0Hz)，7.89(1H，s)，7.72(1H，dd，m)，7.54(1H，d，J＝8.0Hz)，7.26(1H，m.br)，7.20(1H，d，J＝11Hz)，6.71(1H，br s)，3.00(3H，d，J＝5Hz)，2.70(2H，m)，2.52(2H，m)，2.26(1H，m)，1.69(1H，m，br)。Mass spectrum: 443 (M+H
+).
4-[7-(4-cyano group-3-methoxyl group-phenyl)-8-oxo-6-sulfo--5,7-diaza spiro [3,4] octane-5-
Base]-2-fluoro-N-methyl-benzamide (example 6) synthetic
Example 6
Example 6 is to obtain with the reaction by intermediate 10 and 7f of the method for similar synthetic example 1 that (yield: 20%), 7f is that the method with similar synthetic 7a obtains from corresponding aniline reaction.
1H NMR(CDCl
3，500MHz)：δ(ppm)8.39(1H，t，J＝9.0Hz)，7.62(1H，d，J＝8.0Hz)，7.26(1H，m.br)，7.18(1H，d，J＝10.0Hz)，7.10(2H，m)，6.71(1H，br s)，3.97(3H，s)，3.00(3H，d，J＝5Hz)，2.70(2H，m)，2.52(2H，m)，2.26(1H，m)，1.69(1H，br m).。Mass spectrum: 439 (M+H
+).
4-[7-(3,4-dicyano-phenyl)-8-oxo-6-sulfo--5,7-diaza spiro [3,4] octane-5-yl]-2-
Synthesizing of fluoro-N-methyl-benzamide (example 7)
Example 7
Example 7 is to obtain with the reaction by intermediate 10 and 7g of the method for similar synthetic example 1 that (yield: 20%), 7g is that the method (temperature of reaction is 0 ℃) with similar synthetic 7a obtains from corresponding aniline reaction.
1HNMR(CDCl
3，500MHz)：8.39(1H，t，J＝9.0Hz)，8.00(1H，d，J＝2.0Hz)，7.90(2H，m.br)，7.26(1H，m.br)，7.18(1H，dd，J＝11.5，2.0Hz)，6.71(1H，brs)，3.00(3H，d，J＝5Hz)，2.70(2H，m)，2.52(2H，m)，2.26(1H，m)，1.62(1H，m，br)。Mass spectrum: 434 (M+H
+).
Following example is to be similar to the method for synthetic example 1-7, to adopt synthetic the obtaining of mode of parallel chemistry.
Example 8:4-[7-(4-cyano group-3-trifluoromethoxy-phenyl)-8-oxo-6-sulfo--5,7-diaza spiro [3,4] octane-5-yl]-2-fluoro-N-methyl-benzamide.Mass spectrum (ESP): 493 (M+H
+).
Following example is the method for synthesizing example 1 to be similar to, and adopts synthetic the obtaining of mode of parallel chemistry, and wherein aniline intermediate 9 is replaced by other corresponding aniline.
Example 9:4-[5-(3-fluoro-4-methyl-phenyl)-8-oxo-6-sulfo--5,7-diaza spiro [3,4] octane-7-yl]-the adjacent dintrile of benzene.Mass spectrum (ESP): 391 (M+H
+).
The adjacent dintrile of example 10:4-(8-oxo-6-sulfo--5-p-methylphenyl-5,7-diaza spiro [3,4] octane-7-yl)-benzene.Mass spectrum (ESP): 373 (M+H
+).
Example 11:4-[5-(3-fluoro-4-methyl-phenyl)-8-oxo-6-sulfo--5,7-diaza spiro [3,4] octane-7-yl]-2-methoxyl group-benzene nitrile.Mass spectrum (ESP): 396 (M+H
+).
Example 12:2-methoxyl group-4-(8-oxo-6-sulfo--5-p-methylphenyl-5,7-diaza spiro [3,4] octane-7-yl]-the benzene nitrile.Mass spectrum (ESP): 378 (M+H
+).
Example 13:2-methoxyl group-4-[5-(6-methyl-pyridin-3-yl)-8-oxo-6 sulfo--5,7-diaza spiro [3,4] octane-7-yl]-the benzene nitrile.Mass spectrum (ESP): 379 (M+H
+).
Example 14:2-methoxyl group-4-[5-(6-methoxyl group-pyridin-3-yl)-8-oxo-6 sulfo--5,7-diaza spiro [3,4] octane-7-yl]-the benzene nitrile.Mass spectrum (ESP): 395 (M+H
+).
Example 15:4-[5-(4-fluoro-phenyl)-8-oxo-6-sulfo--5,7-diaza spiro [3,4] octane-7-yl]-2-methoxyl group-benzene nitrile.Mass spectrum (ESP): 382 (M+H
+).
Example 16:2-methoxyl group-4-[8-oxo-6-sulfo--5-(4-trifluoromethyl-phenyl)-5,7-diaza spiro [3,4] octane-7-yl]-the benzene nitrile.Mass spectrum (ESP): 432 (M+H
+).
Example 17:4-[5-(4-chloro-phenyl)-8-oxo-6-sulfo--5,7-diaza spiro [3,4] octane-7-yl]-2-methoxyl group-benzene nitrile.Mass spectrum (ESP): 399 (M+H
+).
Example 18:4-[5-(3,4-two fluoro-phenyl)-8-oxo-6-sulfo--5,7-diaza spiro [3,4] octane-7-yl]-2-methoxyl group-benzene nitrile.Mass spectrum (ESP): 400 (M+H
+).
Example 19:4-[5-(3-fluoro-4-cyano group-phenyl)-8-oxo-6-sulfo--5,7-diaza spiro [3,4] octane-7-yl]-2-methoxyl group-benzene nitrile.Mass spectrum (ESP): 407 (M+H
+).
Example 20:2-methoxyl group-4-(8-oxo-6-sulfo--5,7-diaza spiro [3,4] octane-7-yl]-the benzene nitrile.Mass spectrum (ESP): 364 (M+H
+).
Example 21:4-[7-(4-cyano group-3-methoxyl group-phenyl)-8-oxo-6-sulfo--5,7-diaza spiro [3,4] octane-5-yl]-methyl benzoate.Mass spectrum (ESP): 422 (M+H
+).
Example 22:4-[7-(4-cyano group-3-methoxyl group-phenyl)-8-oxo-6-sulfo--5,7-diaza spiro [3,4] octane-5-yl]-ethyl benzoate.Mass spectrum (ESP): 436 (M+H
+).
Example 23:4-[5-(4-methylol-phenyl)-8-oxo-6-sulfo--5,7-diaza spiro [3,4] octane-7-yl]-2-methoxyl group-benzene nitrile.Mass spectrum (ESP): 394 (M+H
+).
Following example is the method for synthesizing example 1 to be similar to, and adopts synthetic the obtaining of mode of parallel chemistry, and intermediate cyclobutanone is wherein replaced by acetone or acetone cyanohydrin.
Example 24:4-[3-(3,4-dicyano-phenyl)-5,5-dimethyl-4-oxo-2-sulfo--imidazolidine-1-yl]-2-fluoro-N-methyl-benzamide.Mass spectrum (ESP): 422 (M+H
+).
Example 25:4-[3-(3-fluoro-4-methyl-phenyl)-4,4-dimethyl-5-oxo-2-sulfo--imidazolidine-1-yl]-the adjacent dintrile of benzene.Mass spectrum (ESP): 379 (M+H
+).
Example 26:4-(4,4-dimethyl-5-oxo-2-sulfo--3-p-methylphenyl-imidazolidine-1-yl]-the adjacent dintrile of benzene.Mass spectrum (ESP): 361 (M+H
+).
Example 27:4-[4,4-dimethyl-3-(6-methyl-pyridin-3-yl)-5-oxo-2-sulfo--imidazolidine-1-yl]-the adjacent dintrile of benzene.Mass spectrum (ESP): 362 (M+H
+).
Example 28:4-[3-(6-methoxyl group-pyridin-3-yl)-4,4-dimethyl-5-oxo-2-sulfo--imidazolidine-1-yl]-the adjacent dintrile of benzene.Mass spectrum (ESP): 378 (M+H
+).
Example 29:4-[3-(4-fluoro-phenyl)-4,4-dimethyl-5-oxo-2-sulfo--imidazolidine-1-yl]-the adjacent dintrile of benzene.Mass spectrum (ESP): 365 (M+H
+).
Example 30:4-[4,4-dimethyl-5-oxo-2-sulfo--3-(4-trifluoromethyl-phenyl)-imidazolidine-1-yl]-the adjacent dintrile of benzene.Mass spectrum (ESP): 415 (M+H
+).
Example 31:4-[3-(4-chloro-phenyl)-4,4-dimethyl-5-oxo-2-sulfo--imidazolidine-1-yl]-the adjacent dintrile of benzene.Mass spectrum (ESP): 382 (M+H
+).
Example 32:4-[3-(3,4-two fluoro-phenyl)-4,4-dimethyl-5-oxo-2-sulfo--imidazolidine-1-yl]-the adjacent dintrile of benzene.Mass spectrum (ESP): 383 (M+H
+).
Example 33:4-[3-(4-cyano group-3-fluoro-phenyl)-4,4-dimethyl-5-oxo-2-sulfo--imidazolidine-1-yl]-the adjacent dintrile of benzene.Mass spectrum (ESP): 390 (M+H
+).
The adjacent dintrile of example 34:4-(4,4-dimethyl-5-oxo-3-phenyl-2-sulfo--imidazolidine-1-yl)-benzene.Mass spectrum (ESP): 347 (M+H
+).
Example 35:4-[3-(3,4-dicyano-phenyl)-5,5-dimethyl-4-oxo-2-sulfo--imidazolidine-1-yl]-methyl benzoate.Mass spectrum (ESP): 405 (M+H
+).
Example 36:4-[3-(3,4-dicyano-phenyl)-5,5-dimethyl-4-oxo-2-sulfo--imidazolidine-1-yl]-ethyl benzoate.Mass spectrum (ESP): 419 (M+H
+).
Example 37:4-[3-(4-methylol-phenyl)-4,4-dimethyl-5-oxo-2-sulfo--imidazolidine-1-yl]-the adjacent dintrile of benzene.Mass spectrum (ESP): 377 (M+H
+).
The external biological activation analysis
Compound involved in the present invention can become androgen receptor antagonists of new generation.Compare with the androgen receptor antagonists bicalutamide that present prostate tumor drug market is the most frequently used, the compound of our first-selection is antagonistic activity and the androgen receptor antagonists minimum or that be difficult to observed agonist activity with more effective androgen receptor.Discussed in the background of invention part as us, the androgen receptor antagonists of highly selective can effectively be used for the treatment of the androgen receptor diseases associated, particularly for the prostate cancer intractable of hormonotherapy sensitivity with hormonotherapy, and comedo and male pattern baldness or the like.When actual clinical was used, compound of the present invention can be to be used in combination separately or with one or more other medicines.
The compounds of this invention to the detection of androgen receptor antagonism (antagonism) and exciting (agonism) effect can by at the prostate cancer cell of hormone-sensitive (such as LNCaP, LAPC4) and the intractable prostate cancer cell of hormone (such as LNCaP-AR, LAPC4-AR, LNCaP C4-2,22RV1, VCaP, LNCaP-AI and LNCaP-abl) confirmed.The cell that we at first select for use, the one, LNCaP, the prostatic cell model of hormonotherapy sensitivity commonly used; The 2nd, 22RV1, the prostatic cell model of hormonotherapy refractory commonly used.They all express androgen receptor, and male sex hormone can be induced its prostate specific antigen (Prostate-SpecificAntigen, expression PSA), and can promote the growth of these cells.Prostate specific antigen is an important physical signs of prostate cancer, be subjected to the regulation and control of androgen receptor, can be used for our compound of being invented of comparison to the antagonistic ability of androgen receptor function so detect the level of prostate specific antigen (PSA) on corresponding prostate cancer cell model, and the growth-inhibiting of cell experiment simultaneously (adopting the MTT method) also can be used for estimating the inhibition ability of the carcinoma of prostate cell growth of these compounds.Further the oral pharmacokinetics of the test compound that we invented on rodents such as mouse and rat preferably to have moving character of medicine and stable compound in the good body, makes it to become the prostate cancer drug candidate with clinical prospect.The effective androgen receptor antagonists of these highly selectivies also can carry out the comparison and the assessment of drug effect in the body at the animal model of prostate cancer, alternative prostate gland corpus carcinosus inner model comprises LNCaP, LAPC4, LAPC9, CWR22, LNCaP-AR, LNCaP C4-2, VCaP, 22RV1, LNCaP-abl and LNCaP-AI are to take into account the prostate cancer clinical practice case intractable with hormone of reaction hormone-sensitive.
Prostate specific antigen (PSA) inhibition test
In order to detect compound that we invent antagonistic activity to androgen receptor, we measure the inhibition activity of these compounds to prostate specific antigen (PSA) on multiple prostate cancer cell, effectively induce the expression of PSA in cell to increase the susceptibility that suppresses experiment with artificial synthetic male sex hormone R1881 (Methyltrienolone, androgen receptor activator).Prostate cancer LNCaP and 22RV1 cell are androgen-dependent cells, all can buy from U.S. culture presevation storehouse (ATCC).These two kinds of cells can and contain 10% foetal calf serum (FBS) at the RPMI RPMI-1640, the penicillin of 100 units per ml, incubation growth in the amphotericin B of the Streptomycin sulphate of 100 mcg/ml and 0.25 mcg/ml, cell need remain on CO2gas incubator to guarantee the growth conditions of 37 ℃ of temperature and 5% carbonic acid gas.Go down to posterity LNCaP cell between 20 to 35 times and the 22RV1 cell that goes down to posterity between 30 to 50 times can be used for this experiment.LNCaP is a kind of cell strain of hormone-sensitive, and the 22RV1 intractable prostate cancer cell strain that is a kind of hormone.In order to detect prostate specific antigen (PSA), at first human prostate cancer LNCaP or 22RV1 cell transfer are cultured to and contain 10% RPMI RPMI-1640 through the foetal calf serum (Charcoal-stripped FBS) of charcoal treatment, cultivate after three days, be allocated in standard 96 porocyte culture plates with the concentration of every Kong Wuqian cell.Next day, in the nutrient solution of every hole, add ultimate density and be the male sex hormone R1881 of synthetic of 50 pmols (pM) concentration and the test compounds or the bicalutamide (compound as a comparison) of finite concentration gradient (ultimate density is the 0.001-10 micro-molar concentration).Continue to cultivate four days after adding compound, with euzymelinked immunosorbent assay (ELISA) (ELISA method) be determined at the supernatant nutrient solution prostate specific antigen (PSA) concentration.The level of enzyme linked immunological (ELISA) the test prostate specific antigen in can the Sensitive Detection cell culture fluid.Concrete experimentation is that adding nutrient solution and standard substance (every hole is 200 microlitres) on antibody-coated 96 orifice plates place the dropping point deck vibrator of maintenance 500-600 rotating speed at room temperature to react two hours this plate, wash 96 orifice plates then five times; Then with damping fluid with one to two ten the HRP binding substances is diluted, be added into each 96 orifice plate again.This 96 hole elisa plate at room temperature shook continuously 30 minutes and washed five times as previous step, added the TMB (3,3 ' of 100 microlitres then, 5,5 '-tetramethyl benzidine, concentration 0.4 grams per liter), then the ELISA vibration is ten minutes, adds 100 microlitre stop buffers and comes stopped reaction.Use the photoabsorption microplate reader to measure ELISA 96 orifice plates at 450 nanometer light waves (650 nanometer light waves as a reference), calculate that according to the resulting typical curve of standard substance that enzyme linked immunological (ELISA) test kit provides each 96 reacting hole is secreted into the concentration of the prostate specific antigen of supernatant nutrient solution, calculate the compound tested and bicalutamide 50 percent inhibition concentration (IC at last the prostate specific antigen (PSA) of the prostate cancer cell 22RV1 of the prostate cancer cell LNCaP of hormonotherapy sensitivity and hormonotherapy refractory
50), its result is as shown in table 1.
Table 1: prostate specific antigen (PSA) test data
| Examples of compounds | LNCaP IC 50(nM) | 22RV1 IC 50(nM) |
| Bicalutamide | 1450 | 4720 |
| Examples of compounds 1 | 580 | 890 |
| Examples of compounds 2 | 510 | 630 |
| Examples of compounds 3 | 610 | 540 |
| Examples of compounds 4 | 450 | 1240 |
| Examples of |
750 | 1530 |
| Examples of compounds 6 | 190 | 210 |
| Examples of compounds 7 | 320 | 350 |
| Examples of compounds 8 | 220 | 250 |
| Examples of compounds 9 | 250 | 340 |
| Examples of |
120 | 180 |
| Examples of compounds 11 | 80 | 210 |
| Examples of compounds 12 | 150 | 260 |
| Examples of compounds 24 | 190 | 320 |
| Examples of |
100 | 190 |
| Examples of compounds 26 | 110 | 290 |
clearly show as table 1, carry out substituent variation at these compounds and can cause compound to the change on the antagonistic activity of androgen receptor with consistent division center.Many compounds such as these instantiation compounds, compare with bicalutamide, no matter be at the hormone-sensitive (LNCaP) or the prostate cancer cell of hormone refractory (22RV1), to the generation of prostate specific antigen (PSA) restraining effect, particularly examples of compounds 6-12 and 24-26, its antagonistic activity to androgen receptor is greatly improved, being expected to becomes aspect the prostate cancer than bicalutamide novel cpd efficiently in treatment, and may for example comedo and male pattern baldness etc. develop into effective medicine in other disease relevant with androgen receptor.
The prostate cancer cell growth inhibition test
Prostate cancer LNCaP and 22RV1 cell can and contain 10% foetal calf serum (FBS) at the RPMI RPMI-1640, the penicillin of 100 units per ml, merisis in the amphotericin B of the Streptomycin sulphate of 100 mcg/ml and 0.25 mcg/ml, when cell reaches 80-90% and converges, the cultivation of going down to posterity.For the compound of testing us growth-inhibiting ability to prostate cancer cell, at first human prostate cancer LNCaP or 22RV1 cell transfer are cultured to and contain 10% RPMI1640 nutrient solution through the foetal calf serum (Charcoal-stripped FBS) of charcoal treatment, cultivate after three days, cell is added on the standard 96 porocyte culture plates in 100 microlitre volumes with every Kong Shiwan number, place the carbonic acid gas cell cultures brooder of 37 ℃ of temperature to spend the night.Carefully remove cell culture fluid, the nutrient solution that adds 80 microlitre preheatings then in every hole, with 10 microlitres the test compounds of finite concentration gradient (ultimate density from 20 to 0.1 micro-molar concentrations) or bicalutamide compound is as a comparison arranged, under 37 ℃ of temperature, kept 30 minutes, the last male sex hormone R1881 (ultimate density is 50 pmols (pM) concentration) that adds 10 microlitre synthetic in every hole then kept 96 hours under 37 ℃ of temperature.When cultivate finishing, add 10 microlitre MTT reaction solutions in every hole, continued under 37 ℃ of temperature culturing cell two to four hours, make being able to fully of reaction of in survivaling cell dyestuff and mitochondrial dehydrogenase, naked eyes can be seen the throw out of purple.Add the washing reagent of 100 microlitres then in every hole of 96 porocyte culture plates, lucifuge kept two hours under the room temperature, detected its absorption at 570nm with microplate reader at last.The inhibition per-cent that is expressed as test compounds of experimental result, the multiple of its increase are to carry out the stdn adjustment in the test number that does not have test compounds to contain the male sex hormone R1881 of synthetic as 100% radix.Calculate 50 percent in view of the above and suppress (IC
50) value, the result is as shown in table 2.
Table 2: cell MTT experimental data
| Examples of compounds | LNCaP IC 50(μM) | 22RV1 IC 50(μM) |
| Bicalutamide | 5.7 | 8.9 |
| Examples of compounds 1 | 3.6 | 3.9 |
| Examples of compounds 6 | 0.9 | 1.2 |
| Examples of compounds 7 | 1.8 | 3.0 |
| Examples of |
0.8 | 2.9 |
| Examples of compounds 12 | 1.5 | 3.9 |
| Examples of compounds 24 | 2.9 | 3.0 |
| Examples of compounds 26 | 2.9 | 3.6 |
With just compare at clinical widely used bicalutamide, no matter the compound that we give an example at table 2 is to produce more efficiently restraining effect to hormone-sensitive prostate cancer cell LNCaP or to the growth of the cell 22RV1 of hormone refractory.These to cancer cells suppress active higher compound for example example 6,10 and 12 be worth us to its stability in vivo and in vitro, suppress prostate cancer in pharmacokinetics behavior and the body and grow into further research of row, to confirm to find to be better than the androgen receptor agonist drug of new generation of bicalutamide.
Oral pharmacokinetic studies
30 of healthy male Balb mouse, fasting is random packet after 12 hours, irritates stomach (50mg/kg) and gives examples of compounds 6.After administration 0.5,1,2.0,4.0,6.0 and 24.0 hours veins get 0.5 milliliter of blood, put centrifugal 10min in the centrifuge tube of heparinization, separate and get blood plasma for sample analysis, we adopt liquid chromatography tandem mass spectrum (LC-MS/MS) to be the drug level in the blood plasma after the administration of interior mark detection assay with Proprasylyte (Propranolol), calculate it pharmacokinetic parameters and absolute bioavailability.The result irritates stomach examples of compounds 6 back Plasma Concentrations and keeps the long residence time (seeing accompanying drawing one), and its main pharmacokinetic parameters is as follows: Cmax is respectively 20.3 μ g/mL; T
MaxBe 4hr; T
1/2Be 41hr; AUC
0-24hBe 367 μ g*hr/mL; AUC
0-∞Be 1154 μ g*hr/mL.AUC according to intravenously administrable
0-∞Calculate, the absolute bioavailability of irritating the stomach preparation is 41%.The preliminary pharmacokinetic of mouse oral administration shows that examples of compounds 6 absorbs comparatively fast in the mouse body, the elimination transformation period is longer, and bioavailability is higher, shows that it can become the oral anticancer drug candidate of ideal.
The metabolic stability of compound
In order further to determine the metabolic stability of compound, we adopt human liver's microsome and a plurality of compound hatching reaction of the present invention, use liquid chromatography tandem mass spectrum (LC-MS/MS) method to detect remaining compound substance then.Compound sample is dissolved in dimethyl sulfoxide (DMSO) (DMSO), and further with reaction buffer dilution, with guarantee dimethyl sulfoxide (DMSO) content in the end reaction mixed solution less than 0.1%.Compound sample and human liver's microsome are spent hybrid reactions 0 to 60 minute 37, and the ice acetonitrile of mark Terfenadine is in different time point (0,5,10,20,30,45,60 minutes) termination reaction in containing with adding.Sample mixture is centrifugal, and (4000rpm 10min) gets clear liquid, and the supernatant liquor of different time points is analyzed with liquid chromatography tandem mass spectrum (LC-MS/MS) method.Determining of metabolic stability by comparing with 0 minute compound concentration at the remaining substance compound of different time points.The result shows that examples of compounds 6 is the most stable, transformation period (T
1/2) greater than 60 minutes, almost not degraded in external human body liver microsomes, and examples of compounds 10 and 12 is in people's hepatomicrosome less stable, transformation period (T
1/2) all be about 11 minutes.
Claims (14)
1. the compound that has following chemical structure of general formula (I)
R wherein
1Be selected from
Wherein R ' is methyl, ethyl or CF
3Y is methyl, CF
3, cyano group or halogen;
Wherein W is Sauerstoffatom or sulphur atom;
R wherein
3And R
4Form C together
3-5Cycloalkyl;
R wherein
2Be phenyl and substituent thereof with following substituted radical:
-C (O) NHR " ,-C (O) OR " ,-SO
2Me ,-SO
2NHR ", cyano group, hydroxyl ,-C (S) NHR ", halogen or 5 to 6 yuan of assorted aromatophores; R wherein " to be selected from be hydrogen atom, C
1-6Alkyl, C
1-6Cycloalkyl or C
1-6Thiazolinyl; Perhaps
R
2Be pyridyl and substituent thereof with following substituted radical:
-C (O) NHR " or halogen; R wherein " to be selected from be hydrogen atom, C
1-6Alkyl, C
1-6Cycloalkyl or C
1-6Thiazolinyl.
2. the compound of claim 1, wherein R
1Be selected from
Wherein R ' is methyl, ethyl or CF
3Y ' is methyl, CF
3
3. the compound of claim 1, wherein R
1Be selected from
Y wherein " be cyano group or halogen.
4. claim 2 or 3 compound, wherein W is a Sauerstoffatom.
5. the compound that has following chemical structure of general formula (II)
Wherein W is Sauerstoffatom or sulphur atom;
R wherein
1' be selected from
Wherein R ' is methyl, ethyl or CF
3Y ' is methyl, CF
3
R wherein
3' and R
4' form C together
3-5Cycloalkyl;
Wherein B is selected from cyano group, methyl, CF
3Or halogen;
Wherein A is selected from-C (O) NHCH
3,-C (O) NH
2,-C (O) OCH
3,-C (O) OCH
2CH
3, cyano group, hydroxyl ,-SO
2Me, methyl ,-SO
2NHMe or-SO
2NH
2
6. the compound that has following chemical structure of general formula (III)
Wherein W is Sauerstoffatom or sulphur atom;
R wherein
3And R
4Form C together
3-5Cycloalkyl;
R wherein
1" be selected from
Y wherein " be cyano group or halogen;
Wherein B is selected from cyano group, methyl, CF
3Or halogen;
Wherein A is selected from-C (O) NHCH
3,-C (O) NH
2,-C (O) OCH
3,-C (O) OCH
2CH
3, cyano group, hydroxyl ,-SO
2Me, methyl ,-SO
2NHMe or-SO
2NH
2
7. claim 5 or 6 compound, wherein W is a Sauerstoffatom.
8. has the compound that is selected from following chemical structural formula
9. the method for each compound in the synthetic claim 1 to 8, it may further comprise the steps:
Make aniline 1 and thiophosgene reaction obtain isothiocyanic acid acyl ester 3;
Obtain intermediate 6 by under the situation that has TMSCN or sodium cyanide to exist, aniline 4 and ketone 5 being dewatered; Perhaps, under the situation that has sal epsom to exist, obtain intermediate 6 with aniline 4 and corresponding ketone cyanalcohol reaction; And
Make intermediate 3 and intermediate 6 reactions obtain the final product thio-hydantoin of chemical structure of general formula I.
10. pharmaceutical composition comprises each described compound or pharmaceutically acceptable salt thereof or solution and pharmaceutically acceptable carrier or thinner among the claim 1-8 that treats significant quantity.
11. the pharmaceutical composition of claim 10 is used for the treatment of purposes in the medicine with the active associated conditions of androgen receptor in preparation.
12. the pharmaceutical composition of claim 10 is used for the treatment of purposes in responsive to hormonotherapy to insensitive patient's the medicine of prostate cancer in preparation.
13. the pharmaceutical composition of claim 10 preparation be used for the treatment of alopecia, regeneration hair medicine in purposes.
14. the pharmaceutical composition of claim 10 is used for the treatment of purposes in the medicine of dark sore and comedo in preparation.
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| CN103159680A (en) * | 2011-12-14 | 2013-06-19 | 爱美尼迪药物有限公司 | Imidazole diketone compound and application thereof |
| JP6262733B2 (en) * | 2012-09-04 | 2018-01-17 | シャンハイ ヘンルイ ファーマスーティカル カンパニー リミテッドＳｈａｎｇｈａｉ Ｈｅｎｇｒｕｉ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｃｏ．， Ｌｔｄ． | Imidazoline derivatives, their production, and their application in medicine |
| TWI522102B (en) * | 2013-04-30 | 2016-02-21 | 長庚醫療財團法人 | Use of composition for manufacturing drugs for treating or prophylactically treating acne |
| CN104003939B (en) * | 2014-06-06 | 2017-07-07 | 山东大学 | Diaryl substitution thiohydantoin class compound and preparation method and application |
| CN110023297A (en) * | 2016-07-08 | 2019-07-16 | 詹森药业有限公司 | Substituted hydantoins and thio hydantoin derivative as androgen receptor antagonist |
| CN107954936B (en) * | 2016-10-17 | 2021-03-19 | 海创药业股份有限公司 | Method for preparing deuterated imidazoldione compound |
| KR102658095B1 (en) | 2017-08-07 | 2024-04-19 | 치아타이 티안큉 파마수티컬 그룹 주식회사 | Diarylthiohydantoin compounds as androgen receptor antagonists |
| CN110746399B (en) * | 2018-07-23 | 2022-04-22 | 上海美志医药科技有限公司 | Compound with androgen receptor degrading activity |
| CN115109031A (en) * | 2021-03-23 | 2022-09-27 | 苏州开拓药业股份有限公司 | Anhydrous polymorphic substances of androgen receptor antagonist, preparation method and application thereof |
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| CN117164520A (en) * | 2022-01-28 | 2023-12-05 | 南京思聚生物医药有限公司 | Androgen receptor antagonist with local action and application thereof |
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| CP03 | Change of name, title or address | ||
| CP03 | Change of name, title or address |
Address after: 215123 Jiangsu Suzhou Industrial Park, Suzhou No. 218 Biological Park nanmu Park research and development building C4-401 Patentee after: Suzhou pharmaceutical Limited by Share Ltd Address before: 215123 Jiangsu Suzhou Industrial Park, No. 218, bio Lake Park, C4-401 Patentee before: SUZHOU KINTOR PHARMACEUTICALS INC. |